Crystal structure of human RIOK2 bound to a specific inhibitor

Open Biol. 2019 Apr 26;9(4):190037. doi: 10.1098/rsob.190037.

Abstract

The RIO kinases (RIOKs) are a universal family of atypical kinases that are essential for assembly of the pre-40S ribosome complex. Here, we present the crystal structure of human RIO kinase 2 (RIOK2) bound to a specific inhibitor. This first crystal structure of an inhibitor-bound RIO kinase reveals the binding mode of the inhibitor and explains the structure-activity relationship of the inhibitor series. The inhibitor binds in the ATP-binding site and forms extensive hydrophobic interactions with residues at the entrance to the ATP-binding site. Analysis of the conservation of active site residues reveals the reasons for the specificity of the inhibitor for RIOK2 over RIOK1 and RIOK3, and it provides a template for inhibitor design against the human RIOK family.

Keywords: 40s; RIO kinase; RIOK2; crystal structure; inhibitor; ribosome assembly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain*
  • Crystallography, X-Ray
  • Humans
  • Molecular Structure
  • Protein Binding
  • Protein Conformation*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • RIOK2 protein, human